SUMMARY OF RESEARCH PROJECT Infections normally elicit an immune response that is sufficiently robust to enable pathogen killing, while also regulated to limit excessive inflammation and tissue damage. However, inappropriate regulation following infection may result in development of chronic inflammation and autoimmunity. This project will help determine how dysregulated T cell responses to specific Borrelia burgdorferi (Bb) and host antigens influence development of Lyme arthritis (LA) and Lyme-associated autoimmunity. Lyme disease, caused by infection with the tick-borne pathogen Bb, is usually effectively treated with antibiotic therapy. However, some patients may develop post-infectious disease manifestations following treatment with antibiotics, including post-infectious LA, which may cause long-term or permanent disability. Immune dysregulation and autoimmunity are possible contributing factors to post-treatment Lyme disease syndromes, which may last months or years after antibiotic therapy. In post-infectious LA, the inflamed synovial lesion is characterized by accumulation of inflammatory cellular infiltrate, autoreactive T and B cell responses, and marked synovial fibroblast proliferation, without any evidence of active infection. These features are similar to the histologic picture seen in other forms of chronic inflammatory arthritis, such as rheumatoid arthritis (RA), the prototypic autoimmune joint disease. The objective of this exploratory R21 proposal is to develop novel immunopeptidomics tools using animal models to identify candidate Bb and self-antigens and to study the biologically relevant antigen presenting cells that together are driving CD4+ T cell autoimmunity in LA. Once this work is complete, we will have established a tractable mouse model of Bb infection-induced autoimmunity, providing the research community resources necessary to rigorously study the foundational parameters of MHC-II induction of autoimmunity to specific self- antigens, which lie at the heart of pathogenesis in LA and other autoimmune diseases where infection is a suspected autoimmune trigger.